US20110046212A1 - Use of oleuropein and derivatives in the treatment of type 2 diabetes mellitus and pathologies associated with protein aggregation phenomena - Google Patents
Use of oleuropein and derivatives in the treatment of type 2 diabetes mellitus and pathologies associated with protein aggregation phenomena Download PDFInfo
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- US20110046212A1 US20110046212A1 US12/736,281 US73628109A US2011046212A1 US 20110046212 A1 US20110046212 A1 US 20110046212A1 US 73628109 A US73628109 A US 73628109A US 2011046212 A1 US2011046212 A1 US 2011046212A1
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- oleuropein
- treatment
- diabetes mellitus
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/70—Carbohydrates; Sugars; Derivatives thereof
- A61K31/7042—Compounds having saccharide radicals and heterocyclic rings
- A61K31/7048—Compounds having saccharide radicals and heterocyclic rings having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin, digitoxin or digoxin
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P3/00—Drugs for disorders of the metabolism
- A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
- A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
Definitions
- This invention relates to the use of oleuropein, specifically oleuropein in non-glycated form, and its derivatives in the treatment of type 2 diabetes mellitus. Furthermore, this invention relates to the use of oleuropein, specifically oleuropein in non-glycated form, and its derivatives both from synthesis and from degradation, in the treatment of pathologies associated with protein aggregation phenomena. Specifically, this invention relates to the use of oleuropein to prepare a pharmaceutical formula for the prophylactic and therapeutic treatment of pathologies connected to or deriving from amyloid deposit.
- NIDDM non-insulin dependent diabetes mellitus
- hIAPP amylin
- Amyloid deposits can be seen in around 90% of NIDDM patients, and are today believed to be one of the main causes of this disease.
- Amylin (hIAPP) is a peptide of 37 amino acids co-secreted with the insulin of the ⁇ cells of the islets in response to a raising of blood glucose concentration. Amylin is marked by limited solubility and a high propensity to generating fibrils, through a several stage nucleation process.
- the subject of this invention is oleuropein for use as medicinal product.
- the subject of this invention is the use of oleuropein and/or its derivatives for the preparation of a pharmaceutical formula as reported in the claims attached.
- the Oleaceae family includes very interesting plants, the most famous of which is the olive ( Olea Europaea subsp. Europaea ).
- the Oleaceae family includes 27 genera and between 400 and 900 different species.
- the olive ( Olea Europaea ) is a fruit plant, and its fruits, olives, are used for their oil.
- Olive oil contains many polyphenols.
- Oleuropein is the secoiridoid polyphenol that, in glycoside form, is characteristic of Oleaceae, and specifically of Olea Europea .
- Secoiridoids are structural derivatives of iridoids (that have a cyclopentane ring that is generally fused to a 6-membered oxygenated heterocyclic ring) for the opening of the cyclopentane ring following oxidation and breakage of a carbon-carbon bond.
- Glycated oleuropein (methyl (4S,5E,6S)-4-[2-[2-(3,4-dihydroxyphenyl)ethoxy]-2-oxoethyl]-5-ethylidene-6-[(2S,3R,4S,5S,6R)-3,4,5-tirhydroxy-6-(hydroxymethyl)oxan -2-yl]oxy-4H-pyran-3-carboxylate) is a single chemical species, well characterised by the molecular weight of 540.51 and the molecular formula C 25 H 32 O 13 . It is hydrosoluble in glycated form, and strongly apolar in non-glycated form.
- Oleuropein hydrolysis caused by the olive glycosidases during ripening and the technological process involved in the extraction of extra-virgin olive oil, triggers the release of the aglycone that splits in the oil phase.
- the Applicant determined the aggregation kinetics of hIAPP, both in the presence and absence of oleuropein aglycone as described previously, by means of the Thioflavin T test (ThT).
- ThT Thioflavin T test
- the ThT test is widely used to monitor the appearance of ⁇ protein and peptide rich oligomers and polymers, and is based on the increase of fluorescence to 485 nm, following excitation to 440 nm, of the ThT when it interacts with amyloid type structures.
- the ThT test has been carried out by using various different concentrations of oleuropein aglycone in order to generate the various molar ratios between this and the peptide.
- the test was carried out by diluting the amylin (originally dissolved in 80-100% hexafluoroisopropanol (HFIP) in sodium phosphate buffer 10 mM pH 7.4 in the presence of 1-4% HFIP, at concentrations of between 3.125 and 12.5 ⁇ M, in the presence or absence of non-glycated oleuropein at concentrations of 0.1 ⁇ , 1 ⁇ , 2 ⁇ , 3 ⁇ and 10 ⁇ of amylin concentration.
- the bulk solution of oleuropein aglycone, redissolved following deglycosylation, in order to obtain 100 mM in dimethyl sulfoxide (DMSO) was further diluted in the same phosphate buffer immediately prior to use, in order to obtain 100 ⁇ of final concentration.
- DMSO dimethyl sulfoxide
- Applicant also carried out a study to clarify the structural changes brought about by the presence of oleuropein during amylin aggregation.
- Circular dichromism analyses were used for this, as this technique allows for the evaluation of secondary structures and the disordered structure of polymers in solution. Spectra were acquired in the region of the distant ultraviolet (between 195 and 295 nm) at 25° C., accumulating 8 successive spectra for each analysis carried out at the scanning speed of 50 nm/min. The difference against the corresponding blank spectrum was noted against each sample spectrum. In practice, immediately after having been dissolved at the concentration of 12.5 ⁇ M in sodium phosphate 10 mM pH 7.4 and 1% HFIP, the amylin is found to be not very structured with a minimal presence of secondary structure.
- the spectrum shows conversion towards a ⁇ -sheet rich structure, marked by a minimum of around 218 nm, with no change to solubility.
- a progressive reduction in signal was noted, due to an incipient precipitation of the hIAPP present in the sample due to the reaching of critical aggregate dimensions of permanence in suspension.
- the transition to ⁇ structure, with a propensity to aggregate is widely inhibited by the presence of the oleuropein at a concentration of 40 ⁇ M.
- a significant reduction in signal intensity can be noted, indicative of precipitation.
- the spectrum shows no characteristics due to the presence of the ⁇ structure.
- non-glycated oleuropein interferes with the amyloid aggregation of hIAPP, inhibiting its transition to a ⁇ structure and, at the same time, causes peptide insolubility.
- Electronic microscope analysis of amylin aggregates obtained in the presence and absence of oleuropein has shown that the precipitate forms in the presence of amorphous oleuropein.
- amylin aggregates were obtained by incubating the peptide at the concentration of 3 ⁇ M in sodium phosphate 10 mM pH 7.4, 1% HFIP in the presence and absence of oleuropein aglycone 30 ⁇ M, at 25° C. for 30 mins., 1 hr, 3 hrs, 5 hrs, 18 hrs, 48 hrs and 72 hrs. At the end, the aggregates were diluted 100 times in the culture medium, and administered to the cells for 24 hrs.
- Treatment cytotoxicity was therefore estimated as a function of the reduction of the MTT colour (bromide of 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium), a test widely used to evaluate cell vitality.
- the colorant administered for 2 hrs at the concentration of 0.5 mg/ml, following mitochondrial reduction, gives rise to the formation of a product that, once solubilised following cell lysis in 20% SDS, 50% N,N dimethylformamide, absorbs at 570 nm.
- SDS 50% N,N dimethylformamide
- the hIAPP aggregates show toxicity levels that decrease as time spent in vitro increases. Starting from 30 mins., it remains statistically significant in these conditions up to 3 hrs.
- the cells exposed to the hIAPP aggregates in the presence of oleuropein did not show any significant sufferance as compared with the untreated controls, and showed a significant recovery of vitality as compared with the cells treated with hIAPP alone.
- Treatment with oleuropein alone did not report any statistically significant differences as compared with the control.
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- Health & Medical Sciences (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Diabetes (AREA)
- Veterinary Medicine (AREA)
- Public Health (AREA)
- General Health & Medical Sciences (AREA)
- Chemical & Material Sciences (AREA)
- Animal Behavior & Ethology (AREA)
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- Hematology (AREA)
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- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
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- Obesity (AREA)
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- Engineering & Computer Science (AREA)
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- Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
Abstract
This invention relates to the use of oleuropein, specifically oleuropein in non-glycated form, and its derivatives in the treatment of type 2 diabetes mellitus. Furthermore, this invention relates to the use of oleuropein, specifically oleuropein in non-glycated form, and its derivatives both from synthesis and from degradation, in the treatment of pathologies associated with protein aggregation phenomena. Specifically, this invention relates to the use of oleuropein to prepare a pharmaceutical formula for the prophylactic and therapeutic treatment of pathologies connected to or deriving from amyloid deposit.
Description
- This invention relates to the use of oleuropein, specifically oleuropein in non-glycated form, and its derivatives in the treatment of type 2 diabetes mellitus. Furthermore, this invention relates to the use of oleuropein, specifically oleuropein in non-glycated form, and its derivatives both from synthesis and from degradation, in the treatment of pathologies associated with protein aggregation phenomena. Specifically, this invention relates to the use of oleuropein to prepare a pharmaceutical formula for the prophylactic and therapeutic treatment of pathologies connected to or deriving from amyloid deposit.
- It is a well known fact that type 2 non-insulin dependent diabetes mellitus (NIDDM) is marked by the presence of pancreatic islets of amyloid substance, which mainly comprises is aggregates of a peptide, amylin (hIAPP).
- Amyloid deposits can be seen in around 90% of NIDDM patients, and are today believed to be one of the main causes of this disease. Amylin (hIAPP) is a peptide of 37 amino acids co-secreted with the insulin of the β cells of the islets in response to a raising of blood glucose concentration. Amylin is marked by limited solubility and a high propensity to generating fibrils, through a several stage nucleation process.
- Scientific research is naturally greatly involved in attempting to identify new molecules able to inhibit the formation of amyloid aggregates of hIAPP, to be used in the prophylactic and therapeutic treatment of NIDDM and in all pathologies associated with protein aggregation phenomena.
- The subject of this invention is oleuropein for use as medicinal product.
- The subject of this invention is the use of oleuropein and/or its derivatives for the preparation of a pharmaceutical formula as reported in the claims attached.
- Preferred forms of this invention are explained and claimed hereto, as reported in the attached dependent claims.
- The Oleaceae family includes very interesting plants, the most famous of which is the olive (Olea Europaea subsp. Europaea). The Oleaceae family includes 27 genera and between 400 and 900 different species.
- The olive, (Olea Europaea) is a fruit plant, and its fruits, olives, are used for their oil. Olive oil contains many polyphenols. Oleuropein is the secoiridoid polyphenol that, in glycoside form, is characteristic of Oleaceae, and specifically of Olea Europea. Secoiridoids are structural derivatives of iridoids (that have a cyclopentane ring that is generally fused to a 6-membered oxygenated heterocyclic ring) for the opening of the cyclopentane ring following oxidation and breakage of a carbon-carbon bond.
- Glycated oleuropein (methyl (4S,5E,6S)-4-[2-[2-(3,4-dihydroxyphenyl)ethoxy]-2-oxoethyl]-5-ethylidene-6-[(2S,3R,4S,5S,6R)-3,4,5-tirhydroxy-6-(hydroxymethyl)oxan -2-yl]oxy-4H-pyran-3-carboxylate) is a single chemical species, well characterised by the molecular weight of 540.51 and the molecular formula C25H32O13. It is hydrosoluble in glycated form, and strongly apolar in non-glycated form.
- Oleuropein hydrolysis, caused by the olive glycosidases during ripening and the technological process involved in the extraction of extra-virgin olive oil, triggers the release of the aglycone that splits in the oil phase.
- In our experimental system, deglycosylation has been applied by incubating 5.5 μmoles of glycated oleuropein (obtained from the company Extrasynthese) in a sodium phosphate buffer 0.1 M pH 7.0 (10 mM final) with 7.55 U.I. of β-almond glucosidase (EC 3.2.1.21). The reaction mixture was therefore centrifuged at 18,000 rpm for 10 minutes, in order to collect the oleuropein aglycone that had become insoluble in an aqueous environment. Mass spectrometer analysis of the precipitate allowed for the determination of product purity. The precipitate was fully redissolved in DMSO and stored in the dark.
- The Applicant was surprised to note that the oleuropein and/or its derivatives had a great capacity to inhibit amylin amyloid (hIAPP).
- The Applicant determined the aggregation kinetics of hIAPP, both in the presence and absence of oleuropein aglycone as described previously, by means of the Thioflavin T test (ThT). The ThT test is widely used to monitor the appearance of β protein and peptide rich oligomers and polymers, and is based on the increase of fluorescence to 485 nm, following excitation to 440 nm, of the ThT when it interacts with amyloid type structures. The ThT test has been carried out by using various different concentrations of oleuropein aglycone in order to generate the various molar ratios between this and the peptide.
- The test was carried out by diluting the amylin (originally dissolved in 80-100% hexafluoroisopropanol (HFIP) in sodium phosphate buffer 10 mM pH 7.4 in the presence of 1-4% HFIP, at concentrations of between 3.125 and 12.5 μM, in the presence or absence of non-glycated oleuropein at concentrations of 0.1×, 1×, 2×, 3× and 10× of amylin concentration. The bulk solution of oleuropein aglycone, redissolved following deglycosylation, in order to obtain 100 mM in dimethyl sulfoxide (DMSO) was further diluted in the same phosphate buffer immediately prior to use, in order to obtain 100× of final concentration. Incubation was carried out at 25° C. and, at various intervals, 50 μL of solution was taken from each mix, which were diluted 8 times in the glycine/NaOH buffer 0.1 M pH 8.5 containing 20 μM ThT. The fluorescence emission value was normalised each time as compared with that of a blank. Each combination of amylin and oleuropein concentrations was tested at least five times, in order to be able to calculate the standard is deviation for each point.
- The results show that inhibition of the amyloid aggregation of the hIAPP is dose dependent. In fact, when a non-glycated oleuropein: hIAPP ratio is used ranging between 2:1 and 10:1, according to the different preparations of hIAPP and non-glycated oleuropein, we obtain almost complete inhibition (greater than 90%) of the formation of positive ThT aggregates.
- Furthermore, the Applicant also carried out a study to clarify the structural changes brought about by the presence of oleuropein during amylin aggregation.
- Circular dichromism analyses were used for this, as this technique allows for the evaluation of secondary structures and the disordered structure of polymers in solution. Spectra were acquired in the region of the distant ultraviolet (between 195 and 295 nm) at 25° C., accumulating 8 successive spectra for each analysis carried out at the scanning speed of 50 nm/min. The difference against the corresponding blank spectrum was noted against each sample spectrum. In practice, immediately after having been dissolved at the concentration of 12.5 μM in sodium phosphate 10 mM pH 7.4 and 1% HFIP, the amylin is found to be not very structured with a minimal presence of secondary structure. After 3 hours, the spectrum shows conversion towards a β-sheet rich structure, marked by a minimum of around 218 nm, with no change to solubility. After 24 hours, a progressive reduction in signal was noted, due to an incipient precipitation of the hIAPP present in the sample due to the reaching of critical aggregate dimensions of permanence in suspension. On the contrary, the transition to β structure, with a propensity to aggregate, is widely inhibited by the presence of the oleuropein at a concentration of 40 μM. At 3 and 24 hours, a significant reduction in signal intensity can be noted, indicative of precipitation. The spectrum, however, shows no characteristics due to the presence of the β structure. Therefore, on the basis of the above-performed experimental tests, it would appear that non-glycated oleuropein interferes with the amyloid aggregation of hIAPP, inhibiting its transition to a β structure and, at the same time, causes peptide insolubility. Electronic microscope analysis of amylin aggregates obtained in the presence and absence of oleuropein has shown that the precipitate forms in the presence of amorphous oleuropein. We are not yet entirely aware of the nature of the interactions between oleuropein and hIAPP. We can reasonably hypothesise that these such interactions are of a hydrophobic nature, and interfere with the interactions of the same nature that can participate in the stabilisation of intermolecular beta structures. Various experiments have also been carried out on rat insulinoma cells (the RIN-5f line) to verify protection against the toxic effect of hIAPP amyloid aggregates by oleuropein. To this end, amylin aggregates were obtained by incubating the peptide at the concentration of 3 μM in sodium phosphate 10 mM pH 7.4, 1% HFIP in the presence and absence of oleuropein aglycone 30 μM, at 25° C. for 30 mins., 1 hr, 3 hrs, 5 hrs, 18 hrs, 48 hrs and 72 hrs. At the end, the aggregates were diluted 100 times in the culture medium, and administered to the cells for 24 hrs. Treatment cytotoxicity was therefore estimated as a function of the reduction of the MTT colour (bromide of 3-[4.5-dimethylthiazol-2-yl]-2.5-diphenyltetrazolium), a test widely used to evaluate cell vitality. The colorant, administered for 2 hrs at the concentration of 0.5 mg/ml, following mitochondrial reduction, gives rise to the formation of a product that, once solubilised following cell lysis in 20% SDS, 50% N,N dimethylformamide, absorbs at 570 nm. Each treatment was carried out on three examples, and control treatments with only oleuropein or only culture medium were also carried out. The experiments were repeated six times, in order to carry out statistical analysis. The hIAPP aggregates show toxicity levels that decrease as time spent in vitro increases. Starting from 30 mins., it remains statistically significant in these conditions up to 3 hrs. The cells exposed to the hIAPP aggregates in the presence of oleuropein did not show any significant sufferance as compared with the untreated controls, and showed a significant recovery of vitality as compared with the cells treated with hIAPP alone. Treatment with oleuropein alone did not report any statistically significant differences as compared with the control. To this regard, we also carried out the treatment with larger doses of oleuropein, up to a concentration of 200 μM, and this was never found to be significantly toxic for these cells.
Claims (13)
1-6. (canceled)
7. Oleuropein in non-glycated form for use as a medical product.
8. Oleuropein in non-glycated form for the treatment of pathologies associated with protein aggregation phenomena.
9. (canceled)
10. Oleuropein according to claim 8 , where treatment is prophylactic and/or therapeutic.
11. Oleuropein according to claim 8 , where the pathology is chosen from those connected or derived from amyloid deposit.
12. Oleuropein according to claim 11 , where the pathology is type 2 diabetes mellitus.
13. Oleuropein according to claim 8 , where oleuropein in non-glycated form is used in the preparation of a pharmaceutical formula for the prophylactic and/or therapeutic treatment of type 2 diabetes mellitus.
14. A method for the treatment of pathologies associated with protein aggregation phenomena, wherein pharmaceutical formulations containing oleuropein in non-glycated form are administered to a patient in need thereof.
15. The method according to claim 14 , wherein said treatment is prophylactic and/or therapeutic.
16. The method according to claim 14 , wherein the pathology is chosen from those connected or derived from amyloid deposit.
17. The method according to claim 14 , wherein the pathology is type 2 diabetes mellitus.
18. The method according to claim 14 , wherein for treating type 2 diabetes mellitus, a pharmaceutical formulation containing oleuropein in non-glycated form is administered to a patient in need thereof.
Applications Claiming Priority (3)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| ITMI2008A000514 | 2008-03-27 | ||
| IT000514A ITMI20080514A1 (en) | 2008-03-27 | 2008-03-27 | USE OF OLEUROPEINE AND ITS DERIVATIVES IN THE TREATMENT OF TYPE 2 DIABETES AND PATHOLOGIES ASSOCIATED WITH PROTEIN AGGREGATION PHENOMENA |
| PCT/EP2009/053596 WO2009118380A1 (en) | 2008-03-27 | 2009-03-26 | Use of oleuropein and derivatives in the treatment of type 2 diabetes mellitus and pathologies associated with protein aggregation phenomena |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| US20110046212A1 true US20110046212A1 (en) | 2011-02-24 |
Family
ID=40292969
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| US12/736,281 Abandoned US20110046212A1 (en) | 2008-03-27 | 2009-03-26 | Use of oleuropein and derivatives in the treatment of type 2 diabetes mellitus and pathologies associated with protein aggregation phenomena |
Country Status (5)
| Country | Link |
|---|---|
| US (1) | US20110046212A1 (en) |
| EP (1) | EP2285388B1 (en) |
| ES (1) | ES2475212T3 (en) |
| IT (1) | ITMI20080514A1 (en) |
| WO (1) | WO2009118380A1 (en) |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN111840154A (en) * | 2020-07-07 | 2020-10-30 | 五邑大学 | Application of oleuropein or jasminum grandiflorum extract in preparing anti-glycosylation preparation |
| US11191744B2 (en) * | 2017-02-16 | 2021-12-07 | Valbiotis | Pharmaceutical active ingredient and use thereof, in particular for the prevention and treatment of metabolic disorders in humans and animals |
Families Citing this family (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| IT201700013599A1 (en) * | 2017-02-08 | 2018-08-08 | Solosale Srl | Pharmaceutical composition for the prevention and treatment of memory and cognitive deficits related to aging |
| WO2019111142A1 (en) * | 2017-12-07 | 2019-06-13 | Università Degli Studi Di Roma "La Sapienza" | Oleuropein for use in reducing post-prandial glycaemia |
Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040097428A1 (en) * | 2002-05-22 | 2004-05-20 | Hamdi Hamdi K. | Methods for inhibiting cancer and scar formation |
| US20060177530A1 (en) * | 2003-07-14 | 2006-08-10 | Roberto Crea | Method of treating diabetes type II |
Family Cites Families (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| KR20050078709A (en) | 2004-01-31 | 2005-08-08 | 삼성전자주식회사 | Method for scalable video coding and decoding, and apparatus for the same |
| KR20050107897A (en) | 2004-05-10 | 2005-11-16 | 주식회사 지엔 | The roof door open/close apparatus for greenhouse |
| KR20050091672A (en) * | 2005-08-26 | 2005-09-15 | 전영수 | Chewing gum composition of containing oleuropein |
| KR20050115451A (en) * | 2005-11-11 | 2005-12-07 | 전영수 | Process for preparing olive candy drops |
| FR2920668B1 (en) | 2007-09-06 | 2010-08-13 | Girex | USE OF OLEOCANTHAL FOR THE TREATMENT OF LIPID METABOLISM DISORDERS |
-
2008
- 2008-03-27 IT IT000514A patent/ITMI20080514A1/en unknown
-
2009
- 2009-03-26 ES ES09726179.6T patent/ES2475212T3/en active Active
- 2009-03-26 EP EP09726179.6A patent/EP2285388B1/en active Active
- 2009-03-26 WO PCT/EP2009/053596 patent/WO2009118380A1/en active Application Filing
- 2009-03-26 US US12/736,281 patent/US20110046212A1/en not_active Abandoned
Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US20040097428A1 (en) * | 2002-05-22 | 2004-05-20 | Hamdi Hamdi K. | Methods for inhibiting cancer and scar formation |
| US20060177530A1 (en) * | 2003-07-14 | 2006-08-10 | Roberto Crea | Method of treating diabetes type II |
Non-Patent Citations (4)
| Title |
|---|
| Bazoti et al., Noncovalent Interaction Between Amyloid-B-Peptide (1-40) and Oleuropein Studied by Electrospray Ionization Mass Spectrometry," J Am Soc Mass Spectrom, 17: 568-575, 2006. * |
| Calis et al., "A secoiridoid glucoside from Fraxinus angustifolia," Phytochemistry, 41(6):1557-1562, 1996. * |
| Komaki et al., "Identification of Anti-alpha-Amylase Components from Olive Leaf Extracts," Food Sci. Technol. Res., 9 (1), 35-39, 2003. * |
| Neddenriep et al., Short Peptides as Inhibitors of Amyloid Aggregation, The Open Biotechnology Journal, 5:39-46, 2011 * |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US11191744B2 (en) * | 2017-02-16 | 2021-12-07 | Valbiotis | Pharmaceutical active ingredient and use thereof, in particular for the prevention and treatment of metabolic disorders in humans and animals |
| CN111840154A (en) * | 2020-07-07 | 2020-10-30 | 五邑大学 | Application of oleuropein or jasminum grandiflorum extract in preparing anti-glycosylation preparation |
Also Published As
| Publication number | Publication date |
|---|---|
| ES2475212T3 (en) | 2014-07-10 |
| EP2285388A1 (en) | 2011-02-23 |
| EP2285388B1 (en) | 2014-03-26 |
| ITMI20080514A1 (en) | 2009-09-28 |
| WO2009118380A1 (en) | 2009-10-01 |
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Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| STCB | Information on status: application discontinuation |
Free format text: ABANDONED -- FAILURE TO RESPOND TO AN OFFICE ACTION |